Adult stem cells can renew themselves at each division and generate terminally differentiated progeny that maintain homeostasis in adult tissues. A major issue in understanding adult stem cells has been to distinguish whether regulation is primarily controlled by internal or external mechanisms. In mammalian systems, stromal cells have been hypothesized to form special microenvironments or niches for stem cells. Due to the difficulty in identifying stem cells and surrounding stem cells in vivo, there is little known about the structure and function of stem cell niches. Recently, we have demonstrated the existence of germline stem cell (GSC) niches in the Drosophila ovary, where stem cells and their surrounding cells can be effectively studied in vivo. We have also identified decapentaplegic (dpp), encoding a TGF-beta-like growth factor, as a key signal from the niche cells regulating GSC self-renewal and division. However, there are still many questions that remain to be answered regarding how the niche regulates GSCs. The long-term goal of this project will be to gain a greater understanding of how the niches regulate stem cells, and of dpp and other signaling pathways involved in the communication between stem cells and their niches, and of intrinsic factors in stem cells that interpret these signals. We will focus on how the dpp pathway regulates GSC self-renewal and differentiation. Our genetic screens have identified mutants that affect GSC self-renewal and differentiation. Further molecular characterization of some of these mutants will reveal important molecular mechanisms regulating GSCs. The mechanisms controlling GSCs in the Drosophila ovary are likely to be fundamental to the understanding of adult mammalian stem cells since stem cells from diverse organisms share similar "stem" properties. In addition, a better understanding of the mechanisms regulating stem cells is of considerable clinical relevance, since the pathways and genes involved will provide valuable information for using stem cells clinically and for treating some degenerative diseases and cancer.